Long-Term Benefits, Risks of Biologic Disease-Modifying Anti-Rheumatic Drugs in Patients with RA

In addition to anti-inflammatory effects, infliximab and adalimumab have also been shown to improve lipid profiles; where infliximab increased both HDL-C and LDL-C panel, adalimumab increased HDL-C with no changes of LDL-C.¹⁵

One study showed that adalimumab reduced aortic stiffness independently of its RA response.¹⁶

Another study showed that lipo­protein(a) (LP[a]) is a risk factor for athero­sclerotic CVD and that the plasma level of LP(a) in RA patients is increased significantly in comparison to the general population. LP(a) cannot be normalized by statin treatment, but can be better controlled by TNF inhibitors. This result indicates a need for TNF inhibitors in RA patients to provide better CVD protection.¹⁷

A systematic review and meta-analysis published in 2011 showed that use of TNF inhibitors was associated with a reduced risk for all cardiovascular events in observational cohort studies; however, there was heterogeneity among the studies and possible publication bias.18 Additionally, the meta-analysis of three randomized, controlled trials showed only a trend, which was not statistically significant, toward decreased risk.18 This meta-analysis included 16 studies that had been conducted prior to 2009, but only 11 studies were included in the meta-analysis.

A study published in 2015 showed that even though anti-TNFs and methotrexate demonstrated reduction in the risk of all CV events, anti-TNFs were superior in reducing risk of myocardial infarctions, strokes and major adverse cardiac events where methotrexate failed to show statistical significance.⁹

A more recent study published in 2016 compared hypertension outcomes between DMARDs and anti-TNFs in a retrospective cohort study using insurance claims data. It demonstrated that TNF inhibitors had no statistical significance over DMARDs in controlling hypertension.¹⁹ The researchers concluded that anti-TNFs were not associated with a reduced risk of incident hypertension compared with cDMARDs.¹⁹

Finally, a retrospective review/examination/audit of the Olmstead County population–based medical records study demonstrated that there has been statistical improvement in CV mortality in each of the past three decades, with the most recent decade having the most apparent improvement.²⁰

Even though the FDA has levied a warning for TNF inhibitors in RA patients with congestive heart failure (CHF), recent studies showed no CHF recurrence or new CHF onset while patients were using TNF inhibitors.^21,22 Only in New York Heart Association class III or IV patient populations does the 2015 ACR RA guideline recommend using sDMARDs, non-TNF biologic or tofacitinib over TNF inhibitors.²³

Moreover, TNF inhibitors still showed positive CVD outcomes in RA patients after balancing risks and benefits. RA patients treated with TNF inhibitors had a lower risk of CVD compared with biologic-naive RA patients. Also, risk of CVD is similar between non-RA patients and RA patients treated with TNF inhibitors.²⁴

Risks of Malignancy

The new EULAR safety recommendations compared the risk for malignancies among patients receiving bDMARDs with the general population, as well as with those patients on sDMARDs, and concluded that there is no increased risk for solid cancers.¹ Patients on bDMARDs had a higher risk for lymphoma and nonmelanoma skin cancer than the general population, but not significantly greater in than patients receiving sDMARDs.¹